Hepatitis C virus (HCV) affects 180 million people worldwide and is the major cause of liver cirrhosis. Approximately 1%-4% of cirrhotic patients may progress to the development of hepatocellular carcinoma. There are six HCV genotypes and more than 50 subtypes worldwide. The most common HCV genotypes in Taiwan are genotypes 1b, 2a, 2b and 3a. Combined peginterferon (pegIFN) plus ribavirin therapy results in a suboptimal sustained virologic response (SVR) and intolerable adverse effects. Administration of a 48-week pegIFN/ribavirin regimen can achieve a SVR rate of 40%-70% in HCV genotype 1 infected patients. In contrast, the SVR rate is approximately 90% for HCV-2 or HCV-3 infected patients treated with pegIFN/ribavirin therapy for 24 weeks. New generation direct acting antiviral agents (DAAs) have fewer side effects and substantially improve the SVR rates up to 90% for HCV genotype 1. However, the high cost of DAAs limits their clinical application. Thus, the pegIFN/ribavirin regimen remains a mainstay of HCV therapy in developing countries.
Many viral and host factors are responsible for the pathogenesis of HCV infection. HCV genotypes (Fried M W, Shiffman M L, Reddy K R, Smith C, Marinos G, Goncales F L, Jr., Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347:975-982), viral loads (Moreno C, Deltenre P, Pawlotsky J M, Henrion J, Adler M, Mathurin P. Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: a meta-analysis. J Hepatol. 2010; 52:25-31), IL-28B polymorphisms (Ge D, Fellay J, Thompson A J, Simon J S, Shianna K V, Urban T J, Heinzen E L, Qiu P, Bertelsen A H, Muir A J, Sulkowski M, McHutchison J G, Goldstein D B. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009; 461:399-401), and a rapid virologic response (RVR) (Ferenci P, Fried M W, Shiffman M L, Smith C I, Marinos G, Goncales F L, Jr., Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Chaneac M, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 K D)/ribavirin. J Hepatol. 2005; 43:425-433) have been proposed as important predictors for the treatment outcome of peginterferon plus ribavirin therapy. However, the reason why a substantial proportion of patients fail peginterferon plus ribavirin therapy remains unclear. Although HCV primarily replicates in hepatocytes, there is evidence that peripheral blood mononuclear cells (PBMCs) can serve as a suitable site for HCV extrahepatic replication (Di Lello F A, Culasso A C, Parodi C, Bare P, Campos R H, Garcia G. New evidence of replication of hepatitis C virus in short-term peripheral blood mononuclear cell cultures. Virus Res. 2014; 191:1-9). PBMCs are also potent producers of interferon to defend against virus invasion.